TY - JOUR
T1 - Dihydropyridine receptors in muscle are voltage-dependent but most are not functional calcium channels
AU - Schwartz, Lawrence M.
AU - McCleskey, Edwin W.
AU - Almers, Wolfhard
N1 - Copyright:
Copyright 2007 Elsevier B.V., All rights reserved.
PY - 1985
Y1 - 1985
N2 - 1,4-Dihydropyridines are a new class of compounds believed to bind specifically and with high affinity to voltage-dependent calcium channels 1-5. They may be the first example of a ligand of use in the extraction1,2 and purification3 of the Ca channel. Although Ca channels and dihydropyridine receptors are found in many tissues, the richest and most convenient source is skeletal muscle4. Functionally, 1,4-dihydropyridines such as nifedipine and nitrendipine block Ca channels6-11; this effect is believed to form the basis for their clinical importance as Ca antagonists in relaxing vascular smooth muscle 6. But where currents through Ca channels can be measured directly7-10, the block has required 100-1,000 times higher concentrations of dihydropyridine than necessary for the saturation of dihydropyridine binding sites1,5. This discrepancy has remained unresolved because the study of pharmacological effects on Ca channels has required intact cells, while it has been difficult to investigate binding in other than cell-free preparations. Here we describe a method for measuring dihydropyridine binding to intact skeletal muscle and we compare our results with voltage-clamp measurements of Ca-channel block. We conclude that less than a few per cent of the binding sites in skeletal muscle represent functional Ca channels, contrary to general belief.
AB - 1,4-Dihydropyridines are a new class of compounds believed to bind specifically and with high affinity to voltage-dependent calcium channels 1-5. They may be the first example of a ligand of use in the extraction1,2 and purification3 of the Ca channel. Although Ca channels and dihydropyridine receptors are found in many tissues, the richest and most convenient source is skeletal muscle4. Functionally, 1,4-dihydropyridines such as nifedipine and nitrendipine block Ca channels6-11; this effect is believed to form the basis for their clinical importance as Ca antagonists in relaxing vascular smooth muscle 6. But where currents through Ca channels can be measured directly7-10, the block has required 100-1,000 times higher concentrations of dihydropyridine than necessary for the saturation of dihydropyridine binding sites1,5. This discrepancy has remained unresolved because the study of pharmacological effects on Ca channels has required intact cells, while it has been difficult to investigate binding in other than cell-free preparations. Here we describe a method for measuring dihydropyridine binding to intact skeletal muscle and we compare our results with voltage-clamp measurements of Ca-channel block. We conclude that less than a few per cent of the binding sites in skeletal muscle represent functional Ca channels, contrary to general belief.
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U2 - 10.1038/314747a0
DO - 10.1038/314747a0
M3 - Article
C2 - 2581141
AN - SCOPUS:0021843849
SN - 0028-0836
VL - 314
SP - 747
EP - 751
JO - Nature
JF - Nature
IS - 6013
ER -